1. Field of the Invention
The present invention relates generally to the fields of gene therapy and cancer therapeutics. More specifically, the present invention relates to a gene therapy of lung tumors and lung premalignancy using a non-viral delivery system.
2. Description of the Related Art
Lung cancer is the leading cause of cancer-related death. It has a nearly 90% mortality with a median patient survival of less than 2 years (D. J. Minna, Adv. in Oncology. 12, 3–8 (1996)). In 1997, it was estimated that a total of 178,100 new patients were diagnosed in the US, and 160,400 died of the disease (S. L. Parker, T. Tong, S. Bolden, P. A. Wingo, CA Cancer J Clin 47: 5–27 (1997)). The major reasons for such dismal prognosis are the lack of effective preventive interventions and therapies for advanced disease. In most cases of clinically diagnosed lung cancer, malignant cells have already spread into lung parenchyma, regional lymph nodes, and/or extrathoracic organs.
Lung cancer arises in a diffusely damaged bronchial epithelium and is preceded by recognizable histological changes. The earliest changes include squamous metaplasia, followed by three grades of dysplasia, carcinoma in situ, microinvasive cancer, and invasive cancer (W. P. Bennett et al., Cancer Res. 53, 4817–4822 (1993)). From a clinical point of view, the best approach to reduce lung cancer mortality may be to effectively identify and treat bronchial malignancies before they become invasive.
Lung cancers are the result of mutations accumulated during a person's life. By the time lung cancer manifests itself clinically, there may be 10 or 20 such accumulated mutations in the lung cancer cells. The loss of function of tumor suppressor genes and the activation of dominant oncogenes play crucial roles in the pathogenesis of lung cancer. Particularly, p53 alterations occur in 30–60% of premalignant bronchial dysplasias and 60–70% of lung carcinomas (W. P. Bennett et al., Cancer Res. 53, 4817–4822 (1993)). Over-expression of p53 can induce growth arrest or apoptosis in many types of cancer cells (A. J. Levine, Cell 88, 323–331 (1997), S. W. Lower, Curr. Opin. Oncol. 7, 547–553 (1995); U. Tormanen et al., Cancer Res. 55, 5595–5602 (1995); Reeve, et al. British J. Cancer. 73,1193–1200 (1996)). These characteristics make p53 a target for lung cancer gene therapy.
Prior gene therapy studies in lung cancer used viral vectors and direct tumor inoculation. Viruses are more efficient than liposomes in transfecting cells but are also more toxic and immunogenic. As a result, repeated administration is unrealistic. In addition, aerosolization of viral preparations may result in infection of healthy individuals if not performed in an isolated area.
The prior art is deficient in the lack of effective means of treating lung cancer. The present invention fulfills this longstanding need and desire in the art.